B7H3 is a member of the B7 family of immune cell modulating molecules. It is expressed on the surface of a wide variety of tumor cells and tumor vasculature including neuroblastoma, melanoma, renal cell cancer, prostate cancer, colorectal cancer, pancreatic cancer, gastric cancer, breast cancer, ovarian cancer and small cell lung cancer[Cancer Res 61:4048-4054 (2001)]. Its expression on normal cells is inhibited by the microRNA, mi R-29, [Cancer Res 69(15):6275-81 (2009)]. In humans the B7H3 protein is expressed in two forms, 21 g and 41 g. B7H3 expression has been correlated with poor prognosis in ovarian, RCC, NSCLC, pancreatic cancer, prostate cancer and colon cancer [Clin. Dev Immunol. 2010(683875): 1-7]. This finding and additional in vitro data have led to the hypothesis that B7H3 expression may inhibit cytotoxic lymphocyte activity [Structure 21(5):707-17 (2013)].
The mouse antibody, 8H9, binds to both the 21 g and 41 g forms of the protein. 1131 radio-conjugates of this antibody have been shown to be effective in reducing the size of neuroblastomas when administered intrathecally in limited human trials [J Neurooncol 97(3):409-18 (2010]. Fusion of a scFv from this antibody to the cytotoxic protein PE38 resulted in a molecule that was effective in eliminating B7H3-express xenografts in mice [Cancer Res 64:1419-24 (2004)]. Other anti-B7H3 antibodies have been developed with an Fc-enhanced component and has shown good reduction of human tumor xenografts in mouse oncology models [Clin Cancer Res 18-(4):3834-45 (2013)]. Given these results and the expression of B7H3 on a wide variety of solid tumors in humans, it would be highly desirable to engineer additional forms of this molecule which are more suitable for use as a human therapeutic. In particular, additional anti-B7H3 antibody binding compounds with decreased dissociation rates from its antibody-antigen complex would lead to better therapeutic compounds.